rs730880280

Variant names:

• chr12-31103726-CAGA-C
• rs730880280
• NM_030653.4:c.2689_2691delAAG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_030653.4(DDX11):​c.2689_2691delAAG​(p.Lys897del) variant causes a conservative inframe deletion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. K897K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DDX11 NM_030653.4 conservative_inframe_deletion, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.15
• Publications: 10 publications found

Genes affected

DDX11 (HGNC:2736): (DEAD/H-box helicase 11) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which is an enzyme that possesses both ATPase and DNA helicase activities. This gene is a homolog of the yeast CHL1 gene, and may function to maintain chromosome transmission fidelity and genome stability. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

DDX11 Gene-Disease associations (from GenCC):

• Warsaw breakage syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_030653.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 12-31103726-CAGA-C is Pathogenic according to our data. Variant chr12-31103726-CAGA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 8370.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030653.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX11	NM_030653.4	MANE Select	c.2689_2691delAAG	p.Lys897del	conservative_inframe_deletion splice_region	Exon 26 of 27	NP_085911.2	Q96FC9-2
	DDX11	NM_001257144.2		c.2684_2686delAAG	p.Glu895del	disruptive_inframe_deletion splice_region	Exon 26 of 27	NP_001244073.1	Q96FC9-1
	DDX11	NM_001413695.1		c.2684_2686delAAG	p.Glu895del	disruptive_inframe_deletion splice_region	Exon 28 of 29	NP_001400624.1	Q96FC9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX11	ENST00000542838.6	TSL:1 MANE Select	c.2689_2691delAAG	p.Lys897del	conservative_inframe_deletion splice_region	Exon 26 of 27	ENSP00000443426.1	Q96FC9-2
	DDX11	ENST00000545668.5	TSL:1	c.2684_2686delAAG	p.Glu895del	disruptive_inframe_deletion splice_region	Exon 26 of 27	ENSP00000440402.1	Q96FC9-1
	DDX11	ENST00000228264.10	TSL:1	c.2611_2613delAAG	p.Lys871del	conservative_inframe_deletion splice_region	Exon 26 of 27	ENSP00000228264.6	Q96FC9-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251348 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000171 AC: 25 AN: 1461426 Hom.: 0 AF XY: 0.0000179 AC XY: 13 AN XY: 727006

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5514

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111896

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Warsaw breakage syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.2
Mutation Taster		=63/37	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730880280; hg19: chr12-31256660;